Most cited article - PubMed ID 33627836
Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics
Fasting induces significant shifts in substrate utilization with signs of acute insulin resistance (IR), while obesity is associated with chronic IR. Nonetheless, both states substantially influence adipose tissue (AT) function. Therefore, in this interventional study (NCT04260542), we investigated if excessive adiposity in premenopausal women alters insulin sensitivity and AT metabolic and endocrine activity in response to a 60-h fast and a subsequent 48-h refeeding period. Using physiological methods, lipidomics, and AT explants, we showed that obesity partially modified AT endocrine activity and blunted the dynamics of AT insulin resistance in response to the fasting/refeeding challenge compared to that observed in lean women. AT adapted to its own excess by reducing lipolytic activity/free fatty acids (FFA) flux per mass. This adaptation persisted even after a 60-h fast, resulting in lower ketosis in women with obesity. This could be a protective mechanism that limits the lipotoxic effects of FFA; however, it may ultimately impede desirable weight loss induced by caloric restriction in women with obesity.
- Publication type
- Journal Article MeSH
This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.
- Keywords
- Acetate, GABA, Hypothalamus, Insulin resistance, PCOS, Pyroptosis,
- MeSH
- Adiponectin metabolism blood MeSH
- Hypoxia-Inducible Factor 1, alpha Subunit * metabolism MeSH
- NF-E2-Related Factor 2 metabolism MeSH
- Follicle Stimulating Hormone blood MeSH
- gamma-Aminobutyric Acid metabolism MeSH
- Gonadotropin-Releasing Hormone metabolism MeSH
- Hypothalamus * metabolism drug effects pathology MeSH
- Insulin Resistance MeSH
- Rats MeSH
- Leptin blood metabolism MeSH
- Letrozole pharmacology MeSH
- Luteinizing Hormone blood MeSH
- Disease Models, Animal MeSH
- Rats, Wistar * MeSH
- Pyroptosis * drug effects MeSH
- Polycystic Ovary Syndrome * chemically induced metabolism drug therapy pathology MeSH
- Testosterone blood MeSH
- Triglycerides blood metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Adiponectin MeSH
- Hypoxia-Inducible Factor 1, alpha Subunit * MeSH
- NF-E2-Related Factor 2 MeSH
- Follicle Stimulating Hormone MeSH
- gamma-Aminobutyric Acid MeSH
- Hif1a protein, rat MeSH Browser
- Gonadotropin-Releasing Hormone MeSH
- Leptin MeSH
- Letrozole MeSH
- Luteinizing Hormone MeSH
- Nfe2l2 protein, rat MeSH Browser
- Testosterone MeSH
- Triglycerides MeSH
Since the 1950s, one of the goals of adipose tissue research has been to determine lipolytic and lipogenic activity as the primary metabolic pathways affecting adipocyte health and size and thus representing potential therapeutic targets for the treatment of obesity and associated diseases. Nowadays, there is a relatively large number of methods to measure the activity of these pathways and involved enzymes, but their applicability to different biological samples is variable. Here, we review the characteristics of mean lipogenic and lipolytic enzymes, their inhibitors, and available methodologies for assessing their activity, and comment on the advantages and disadvantages of these methodologies and their applicability in vivo, ex vivo, and in vitro, i.e., in cells, organs and their respective extracts, with the emphasis on adipocytes and adipose tissue.
- Keywords
- acetyl-CoA carboxylase, activity measurement, adipose triglyceride lipase, fatty-acid synthase, hormone-sensitive lipase, inhibitor,
- MeSH
- Humans MeSH
- Lipogenesis * MeSH
- Lipolysis * MeSH
- Obesity metabolism MeSH
- Adipose Tissue metabolism MeSH
- Adipocytes metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.
